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Glomerulonephritis

Glomerulonephritis

What is it?

Glomerulonephritis is a group of kidney diseases characterized by inflammation of the filtering units of the kidney called glomeruli.  When inflamed these glomeruli allow passage of protein and blood into the urine.  Left untreated this chronic inflammation can lead to scarring, loss of kidney function, high blood pressure, and kidney failure requiring dialysis or transplantation.

What are the different types of glomerulonephritis?

Glomerulonephritidies are classified based on the microscopic appearance of the affected kidney tissue under the microscope.  Each of these entities can be associated with high blood pressure, progressive kidney failure, edema, high cholesterol and anemia.

The specific names of the various glomerulonephritidies are listed below:

-          Focal and Segmental Glomerulosclerosis

-          Minimal Change Disease

-          Membranous Glomerulonephritis

-          Membranoproliferative Glomerulonephritis

-          IgA Neprhopathy

-          Pauci-Immune Glomerulonephritis

-          Crescentic glomerulonephritis

How do you treat glomerulonephritis ?

Treatment of Glomerulonephritis is aimed at decreasing the inflammation at the level of the glomerulus with the goal of stopping the destruction of these filtering units. Corticosteroids have been the primary agents used for most of these diseases.  Manufactured under the names of prednisone or methylprednisilone, these agents are non-specific anti-inflammatory agents and affect many tissues within the body.  Although  effective, in many patients, at high doses, for long periods of time, these agents have significant side affects including : weight gain, hyperglycemia, and agitation, destruction of bones, easy bruising, and thinning of the skin.

Because of these significant side affects many patients are unable to tolerate this form of treatment .  For these reasons researchers within this division have focused on other immunosuppressive drugs that can be used either alone or in combination with corticosteroids, allowing for lower, more tolerable doses , with fewer side affects and better outcomes.

Mycophenolate Mofetil ( Cell Cept) was first used by researchers at Johns Hopkins to treat patients with a variety of glomerulonephritidies.  This drug was designed to prevent a patient’s body from attacking a transplanted organ such as a kidney or liver. The drug targets a specific type of white blood cell that is responsible for attacking the transplanted organ.  This specific type of white blood cell is also responsible for initiating the inflammatory response in patients with glomerulonephritis.  Our initial results with this drug are very encouraging.  In most but not all patients , we were able to eliminate prednisone or methyprednisilone while achieving a partial or complete remission of the glomerulonephritis.  Unlike corticosteroids, the drug is well tolerated .  Stemming from this research The National Institute of Health has initiated large scale multicenter trials comparing Cell Cept to corticosteroids for one of the most difficult to treat glomerulonephritidies.

Other agents that are currently used for treating glomerulonephridities include other drugs that target the immune system.  Like Cell Cept these agents have been designed to prevent rejection in solid organ transplants. These drugs include cyclosporine or Prograf.  Both of these agents are highly effective in treating glomerulonephritis but also carry the unwanted risk of kidney damage.  Little is known regarding the dosage or duration of these agents. Alternatively drugs used to treat cancers of the blood ( leukemia’s) have been used to treat glomerulonephridities.  Like corticosteroids, these agents target many cells of the body and therefore possess many potential side affects.

What type of research in Glomerulonephritis is currently being conducted at Johns Hopkins?

  1. Longitudinal Cohort Study:  Patients who have a biopsy proven diagnosis of  glomerulonephritis and treated by a Johns Hopkins Nephrologists are entered into a data base.  Treatment ( type, duration, and dose) are recorded along with clinical outcomes such as degree of proteinuria, kidney function and side affects.  This data base is utilized to analyze response to treatment  ( by disease ) and attempts to define optimum dose and duration of therapy.

  2. Mycophenolate Mofetil therapy for IgA Nephropathy:  Researchers within the division of nephrology are collaborating with investigators throughout the country to study the effect of Mycophenolate Mofetil on the quantity of proteinuria and kidney survival in patients with IgA ephropathy.

Questions Remain

Although we have made significant progress over the last 10 years significant questions remain.  We still do not know why some patients with the exact same disease respond while others only partially respond or do not respond at all.  Are there underlying genetic factors that determine response rates ? Do some patients need more or less immunosuppressive medications ? Are there some patients that we should not treat ?

Future Studies:

  1. “Relationship Between Gene Expression Profiling and Responses to steroid Treatment in Glomerular Disease Patients

    This study will attempt to answer the question of what underlying genetic factors affect response rates of patients with glomerular disease to immunosuppressive therapy.  With The Human Genome project now completed, the technology exists to rapidly look at ones genetic makeup.  By extracting DNA and RNA from either kidney tissue or White Blood Cells it is possible to analyze the genetic makeup of patients who respond to therapy vs. those who do not.  It is hoped that specific genes can be identified that affect response to therapy.  Once identified physicians can predict response rates prior to administration of potential toxic medications.
  2. “In vitro immune cell function assays predict response of patients with glomerulonephritis to immunosuppressive agents.”

    Commercially available test kits are now available to determine how immunosuppressed any given patient is at a given time.  Our current approach to treating glomerulonephritis is to place every patient with the same type of glomerulonephritis on the same amount of immunosuppressant drug.  This assumes every patient's immune system is the same. An assumption we know not to be true.  It is now possible to isolate patient’s white blood cells and place in tissue culture.  By challenging these white blood cells with various chemicals we can determine how immune compromised or immune competent they are. We would like to study patients with glomerulonephritis and perform this assay on a monthly basis and determine if this particular assay predicts response to immunosuppressive drugs. If our hypothesis is correct we will be able to dose immunosuppressive drugs on an individual basis therefore minimizing toxicity of medication while maximizing the response to medication.
  3. The development of a web enabled data base to assist community nephrologists with treatment of patients with glomerulonephritis.

Hopkins nephrologists have an extensive experience in treating patients with glomerulonephritis.  We some time lose sight of the fact that glomerulonephritis is a rare disease.  Nephrologists in the community may only see 1-2 cases of glomerulonephritis per year and must base therapeutic decision on data that has been published and maybe 5-10 years old. We would like to develop a wed enabled, interactive data base that would be available to community nephrologists.  The Web site could provide a menu of treatment protocols and provide immediate feedback with success rates, dosing schedules and monitoring suggestions.  We would then expect the nephrologists to register their patients in the data base and provide longitudinal feedback on a variety of clinical outcomes and complications. This data would be constantly used to update current information on treatment recommendations and greatly expand the number of patients from which we can make these treatment decisions.

Glomerulonephritis Publications from Johns Hopkins Nephrology:

Briggs W, Tana S, Choi M, Scheel P, Nadasdy T, Racusen L.  Clinicopathologic correlates of prednisone treatment of HIV Associated Nephropathy.  Am J Kid Dis 28(4)618-621, 1996

Briggs W, Gao Z, Gimenez L, Scheel P, Choi M, Burdick J.  Lymphocyte responsiveness to glucocorticoids, cyclosporine or both.  J Clin Pharm. 36:707-714, 1996.

Briggs W, Gao Z-H, Xing JJ, Gimenez L, Samaniego M, Scheel P, Choi M, Burdick J.  Suppression of lymphocyte interleukin-2 receptor expression by glucocorticoids and/or cyclosporine.  J Clin Pharm 36:931-937, 1996.

Briggs W, Eustace J, Mathew S, Gimenez L, Choi M, Scheel P, Burdick J.  Pentoxifylline potentiates in vitro lymphocyte suppression by glucocorticoids and immunosuppressive drugs.  J Clin Pharm 38:561-566, 1998.

Briggs W, Choi M, Scheel P.  Successful treatment of glomerular disease with mycophenolate mofetil.   American Journal of Kidney Disease 31:213-217, 1998

Briggs W, Eustace J, Gimenez LF, Choi MJ, Scheel PJ, Burdick JF.  Lymphocyte suppression by glucocorticoids with cyclosporine, tacrolimus, pentoxifylline and mycophenolate acid.  J. Clin. Pharm. 39:125-130, 1999

Briggs WA, Wu Q, Orgul O, Choi M, Scheel PJ, Burdick J. Lymphocyte suppression by rolipram with other immunosuppressive drugs. J Clin Pharmacol. 39:794-799, 1999

Briggs WA, Gimenez LF, Samaniego-Picata M, Choi MJ, Nadasdy T, Eustace J, Scheel PJ.  Relationship between lymphocyte and clinical steroid responsiveness in focal segmental glomerulosclerosis.  J. Clin. Pharmacol 40, 115-123, 2000.

Eustace J, Neurmberger E, Choi M, Scheel P, Briggs W.  Cohort study of the treatment of HIV associated  nephropathy with corticosteroids.  Kidney International  40, 1253-1260, 2000.

Choi M, Eustace J, Gimenez L, Atta M, Scheel P, Sothinathan R, Briggs W.  Mycophenolate mofetil treatment for primary glomerular diseases.  Kidney International. 61, 1098-1114, 2002.

 

 

 

 

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